Aromatase Inhibitors in Pulmonary Vascular Complications of Liver Disease

Steven M. Kawut，医学博士，理学硕士是医学和流行病学的副教授，在大学， 宾夕法尼亚医学院（Penn），致力于患者的研究和护理 肺血管疾病（PVD）。他对这一领域的兴趣始于他的早期训练，并指导了他的 从那以后的发展。他领导了一个联邦资助的研究项目，该项目基于流行病学和 治疗PVD和右心室功能障碍。他还指导了29多名学员， 在以患者为导向的研究（POR）的成功，导致出版物和资金，因为他们发展到他们的 自己的独立性。 博士Kawut最近被宾夕法尼亚大学招募来指导肺血管疾病项目，这创造了一个 这是一个重要的机会，可以扩大他的研究计划，以及培训和指导年轻的研究人员。 宾夕法尼亚大学的心血管研究所、肺、过敏和 重症监护部和临床流行病学和生物统计学中心提供给候选人， 他的实习生。其中包括最先进的临床研究和实验室资源。候选人： 该奖项的近期和长期职业目标集中在获得临床试验技能上 在罕见的肺静脉疾病和发展他的导师能力。宾夕法尼亚大学的环境非常适合发展 申请人作为导师，并促进学员在这些领域的学术成长。 肺动脉高压发生在4 - 8%的门脉高压患者（称为肺动脉高压）中。 门脉高压（PPHTN））。PPHTN没有已知的发病机制，局限性，非特异性 治疗，并可能大大复杂化，延迟或阻止肝移植。肝肺综合征 (HPS)其特征在于肺微血管扩张和气体交换受损， 30%的患者正在接受肝移植评估。HPS发展的机制是 同样神秘。 博士Kawut最近进行了一项由NIH资助的研究，重点是临床和遗传决定因素， PPHTN和HPS。这些研究表明，1）女性性别是PPHTN的一个强有力的危险因素，2）遗传 雌激素受体的变异与HPS的发生有关，3）β 芳香化酶与较高的血浆雌二醇（E2）水平和较高的PPHTN风险相关。这些 数据有力地表明雌激素是治疗和预防这些疾病的潜在治疗靶点。 门脉高压的肺血管后遗症。 阿那曲唑（AN）是FDA批准的芳香化酶抑制剂， 男性和绝经后女性的雌激素产生。因此，我们建议进行两次原则性证明。 开始随机临床试验（RCT）研究AN抑制雌激素治疗 PPHTN和HPS。我们的目的是：1）确定AN与安慰剂在患者中三个月的效果 2）确定AN与安慰剂相比在HPS患者中三个月内的效果。 终点将包括E2水平、经胸超声心动图测量、肺泡-动脉血氧梯度、 功能状态、安全性和耐受性。 如果提示获益，则结果可用于计划和支持AN的多中心II期或III期RCT 在这些PVD中的一个或两者中。这项研究将为年轻的研究人员提供理想的培训基地 对PVD中的POR感兴趣，希望研究孤儿疾病的新疗法。

Steven M. Kawut, MD, MS is an Associate Professor of Medicine and Epidemiology at the University of Pennsylvania School of Medicine (Penn) who has committed his career to the research and care of patients with pulmonary vascular disease (PVD). His interest in this area began early in his training and has guided his development since then. He heads a federally-funded research program based on the epidemiology and treatment of PVD and right ventricular dysfunction. He has also mentored more than twenty-nine trainees to success in patient-oriented research (POR), resulting in publications and funding as they develop towards their own independence. Dr. Kawut¿s recent recruitment to Penn to direct the Pulmonary Vascular Disease Program has created a significant opportunity to expand his research program as well as to train and mentor young investigators. There are outstanding resources at Penn housed in the Cardiovascular Institute, the Pulmonary, Allergy, and Critical Care Division, and the Center for Clinical Epidemiology and Biostatistics available to the candidate and his trainees. These include state-of-the-art clinical research and laboratory resources. The candidate¿s immediate- and long-term career goals during this award center on acquiring skills in performing clinical trials in rare PVDs and developing his mentorship abilities. The environment at Penn is ideal to develop the applicant as a mentor and to foster the academic growth of mentees in these areas. Pulmonary arterial hypertension occurs in 4-8% of patients with portal hypertension (termed portopulmonary hypertension (PPHTN)). PPHTN has no known disease mechanism, limited, non-specific therapies, and may greatly complicate, delay, or prevent liver transplantation. Hepatopulmonary syndrome (HPS) is characterized by pulmonary microvascular dilations and impaired gas exchange and is found in up to 30% of patients being evaluated for liver transplantation. The mechanism for the development of HPS is similarly cryptic. Dr. Kawut recently performed a NIH-funded study focused on the clinical and genetic determinants of PPHTN and HPS. These studies showed that 1) female gender was a strong risk factor for PPHTN, 2) genetic variation in estrogen receptor β was associated with the occurrence of HPS , and 3) genetic variation in aromatase was associated with both higher plasma estradiol (E2) levels and a higher risk of PPHTN. These data strongly suggest estrogen as a potential therapeutic target in treatment and prevention of these pulmonary vascular sequelae of portal hypertension. Anastrozole (AN) is an FDA-approved aromatase inhibitor which dramatically decreases peripheral estrogen production in men and post-menopausal women. We therefore propose to conduct two ¿proof-ofprinciple¿ randomized clinical trials (RCTs) to begin the study of estrogen inhibition with AN for the treatment of PPHTN and HPS. We aim: 1) To determine the effects of AN versus placebo over three months in patients with PPHTN and 2) To determine the effects of AN versus placebo over three months in patients with HPS. End points will include E2 levels, transthoracic echocardiology measures, alveolar-arterial oxygen gradient, functional status, safety, and tolerability. If suggestive of benefit, the results could be used to plan and power multicenter Phase II or III RCTs of AN in one or both of these PVDs. This research would provide the ideal training ground for young investigators interested in POR in PVD who wish to study novel therapeutics for ¿orphan¿ diseases.